CN104418818B - Parecoxib sodium anhydrous compound - Google Patents
Parecoxib sodium anhydrous compound Download PDFInfo
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- CN104418818B CN104418818B CN201310395826.8A CN201310395826A CN104418818B CN 104418818 B CN104418818 B CN 104418818B CN 201310395826 A CN201310395826 A CN 201310395826A CN 104418818 B CN104418818 B CN 104418818B
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- parecoxib sodium
- anhydrous compound
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- parecoxib
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention belongs to the technical field of medicines and in particular relates to a parecoxib sodium anhydrous compound and a preparation method thereof. The parecoxib sodium anhydrous compound is basically anhydrous and not solvated and has the advantages that the chemical purity is 99.9 percent, the maximum impurity is smaller than one thousandth, the optical purity reaches up to 99.96 percent ee, and the stability is good. The invention also relates to application of a composition of parecoxib sodium in preparing a medicament for treating cyclooxygenase-2(COX-2) mediated diseases.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to Parecoxib Sodium anhydrous compound and preparation method thereof, this
Answering in the bright medicine further relating to use compositions manufacture treatment Transitional cell carcinomas (COX-2) of this compound to mediate disease
With.
Background technology
Pain is the Physiological Psychology activity of a kind of complexity, is one of the most modal symptom.It includes that nocuity stings
Swash the pain feel acted on caused by body, and the pain of noxious stimulation is reacted by body.The pain sensation can be hindered as body
A kind of warning of evil, causes the protection reaction of body series of defence, is the symbol of danger signal, promotes people's urgent action,
Hedging goes evil.Postoperative pain refers to the acute pain that Post operation occurs, usually nociceptive pain, general persistently within 7 days,
It is pain that is the most common and that need emergent management.Postoperative pain is that body is to the one caused by disease itself and operation wound
Complicated physiological reaction, although this kind of durante dolors is shorter, but relatively violent, the operation that especially wound is big, easily give patient
Cause spiritual strike, but also affect the function of each system of whole body, the complication that some are serious can be caused, even cause tight
Weigh accident or jeopardize the life of patient.
Nonsteroidal antiinflammatory drug (NSAIDs) is widely used in treatment inflammation and pain, and the common mechanism of action of this type of medicine is
Suppress the synthesis of internal prostaglandin.Advantage is that analgesic effect is medium without additive；Shortcoming is stimulating gastrointestinal road, easily causes stomach
Mucosal bleeding or induced ulcer.Can be applicable to minor operation, but invalid to treatment of traumatic pain and Encelialgia.Common infusions analgesic
In thing, paracetamol injection determined (recommended dose is 1000mg/6 hour or 650mg/4 hour) and ibuprofen injection (push away
Recommending dosage is 400mg-800mg/6 hour) side effect is less, but dosage is relatively big, and effectiveness is poor；Ketorolac, fluorine compare Lip river
Fragrant ester, lornoxicam, as non-selective COX inhibitor, have serious gastrointestinal untoward reaction, and affect renal function, and its anti-blood
Platelet aggregation adds the danger of wound bleeding.Former times dry goods medicine is as high selectivity cox 2 inhibitor, because of to gastrointestinal
Road impact is little and does not suppress hematoblastic function to be widely popularized, but patient cannot swallow sometimes, or clinical needs are quickly
Onset, such as acute pain patient after Post operation particularly gastrointestinal surgery, celecoxib can not meet as oral drugs and faces
Bed demand.And Parecoxib is mainly used in postoperative acute pain as the first former times dry goods injection, can not be administered orally patient's
Treatment.
Injection Parecoxib Sodium is that first developed by Pfizer can intravenously administrable (IV) and intramuscular injection
(IM) specific cox 2 inhibitor, in March, 2002 Europe listing, trade name: special resistance to®, approval listing specification be 20mg and
40mg.Injection Parecoxib Sodium is for the short term therapy of postoperative pain.
Parecoxib Sodium, molecular formula: C19H17N2O4SNa, structural formula is as follows:
Parecoxib Sodium structural formula
Chemical name: N-[[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl] propionamide sodium salt
The method disclosing synthesis Parecoxib Sodium in patent US5932598, but this patent only discloses its fusing point is
271.5-272.7 DEG C, the crystalline texture of Parecoxib Sodium is characterized.In general, anhydrous nonsolvated forms
Physical stability is better than solvate and hydrate, and therefore this area needs the crystal formation anhydrous, non-solvated of Parecoxib Sodium.
The Parecoxib sodium crystal that the present invention obtains on the basis of great many of experiments, has the advantage that: purity is high, maximum miscellaneous
Matter is less than 1 ‰；Optical purity is high, good stability, even if moisture absorption weightening finish is the most inconspicuous under high humidity conditions.
Summary of the invention
One object of the present invention, discloses a kind of Parecoxib Sodium anhydrous compound crystal.
Another object of the present invention, discloses the preparation method of Parecoxib Sodium anhydrous compound crystal.
A further object of the present invention, discloses the pharmaceutical composition comprising Parecoxib Sodium anhydrous compound.
The invention also discloses Parecoxib Sodium anhydrous compound in manufacturing the medicine of disease for the treatment of COX-2 mediation
Application.
In conjunction with the purpose of the present invention, present invention is specifically described.
The invention provides a kind of Parecoxib Sodium anhydrous compound (shown in formula I)
(I)
This Parecoxib Sodium anhydrous compound crystal, uses D/Max-2500.9161 type x-ray diffractometer to measure, measures
Condition: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak (2 θ) and D value are as follows:
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and has allowed one
Fixed rational range of error, its range of error is ± 0.2 °.
When infrared spectrogram measures, the correction polystyrene film of instrument, meets the regulation of Chinese Pharmacopoeia.
This crystal formation infrared spectrogram (KBr pressed disc method mensuration), at 3242.09 ± 5 cm-1、3034.55±5 cm-1、
1337.58±5 cm-1With 1064.18 ± 5cm-1There is characteristic peak at place.
The fusing point of this crystal formation is 273 DEG C 273.5 DEG C, measures by the method for Chinese Pharmacopoeia, and this is those skilled in the art
Well known.
Another object of the present invention, discloses the preparation method of Parecoxib Sodium anhydrous compound crystal,
Specifically include the following step:
Parecoxib Sodium is added in 4-5 times of (weigh-volume ratio) heptane, do not put into crystal seed, use vigorous magnetic stirring
Being heated to reflux by the suspension of acquisition 6 hours, be collected by vacuum filtration crystal, at 40 DEG C, dried in vacuum overnight obtains.
Parecoxib Sodium used, the method synthesis that list of references US5932598A provides, the Parecoxib Sodium of synthesis, it
Chemical constitution is through determination of elemental analysis, it was demonstrated that chemical constitution is correct.
A further object of the present invention, it is provided that comprise anhydrous compound crystal and one or more medicines of Parecoxib Sodium
The compositions of the Parecoxib Sodium anhydrous compound of acceptable carrier composition on.
The pharmaceutical composition preparation of the present invention is as follows: uses standard and conventional technique, makes the compounds of this invention and preparation
On, acceptable solid or liquid-carrier combine, and are allowed at random acceptable adjuvant and excipient with on galenic pharmacy
In conjunction with being prepared as microgranule or microsphere.Said composition is used for preparing injection.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount of compound used or concentration are in a wider scope
Regulation, the weight range of reactive compound is the 1%-30%(weight of compositions).
The anhydrous compound crystal that present invention also offers Parecoxib Sodium is manufacturing treatment Transitional cell carcinomas (COX-2) Jie
Application in the medicine of the disease led.
Testing through animal (male rat), the swollen model of Carrageenan foot, adjuvant arthritis model and operation cause
Pain model gives Parecoxib Sodium, and experimental result shows: crystal formation of the present invention and Parecoxib Sodium unformed powder group antipyretic-antalgic
Usefulness is all obvious than matched group, the no significant difference (P > 0.05) between two medication groups.
Stability test
The stability of the crystal formation of the present invention is studied by inventor, and investigation condition is high temperature (60 DEG C ± 2 DEG C), high light
Irradiating (4500Lx ± 500lx), high humidity (92.5% ± 5%) inspection target is outward appearance, content and have related substance.
Result: from 0 10 days under high light, high temperature, super-humid conditions, outward appearance, there are related substance, content not to change, explanation
Chemical stability is good, is suitable for manufacture and the long term storage of pharmaceutical preparation.
Detailed description of the invention:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from this
Invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
Parecoxib Sodium used in the present invention, the method synthesis that list of references WO2003029230 provides, the handkerchief of synthesis
Auspicious former times cloth sodium, purity 98.3% (HPLC normalization method), optical purity 99.1%ee, its chemical constitution through determination of elemental analysis,
Prove that chemical constitution is correct.
Elementary analysis result:
Measured value (value of calculation), C:58.08 (58.10), H:4.23 (4.33), N:7.16 (7.14),
S:8.23 (8.15), Na:5.88 (5.86)；
Prove that chemical constitution is correct.
Embodiment 1
Equipped with stirring, thermometer, condenser 500ml reaction bulb in, add 60 grams of Parecoxib Sodiums and 300 milliliters
Heptane, uses vigorous magnetic stirring to be heated to reflux 6 hours by the suspension of acquisition, is collected by vacuum filtration crystal, at 40 DEG C
Lower dried in vacuum overnight obtains Parecoxib Sodium anhydrous compound, and chemical purity reaches 99.9%, and optical purity reaches 99.96%.
Elementary analysis result:
Measured value (value of calculation), C:58.04 (58.10), H:4.25 (4.33), N:7.12 (7.14),
S:8.21 (8.15), Na:5.98 (5.86)
X-ray powder diffraction characteristic absorption peak (2 θ) and D value are as follows:
| Spectral line number | 2 θ angle (°) measured values | D() measured value | I/I0 |
| 1 | 4.50 | 20.61 | 75 |
| 2 | 7.28 | 11.13 | 81 |
| 3 | 9.13 | 9.72 | 42 |
| 4 | 12.62 | 9.53 | 22 |
| 5 | 12.71 | 8.32 | 100 |
| 6 | 13.50 | 7.79 | 8 |
| 7 | 14.55 | 7.62 | 13 |
| 8 | 14.92 | 6.82 | 14 |
| 9 | 15.12 | 6.24 | 9 |
| 10 | 16.44 | 5.58 | 8 |
| 11 | 16.50 | 5.17 | 4 |
| 12 | 17.15 | 4.83 | 1 |
| 13 | 18.34 | 4.57 | 26 |
| 14 | 19.87 | 4.34 | 1 |
| 15 | 20.10 | 4.31 | 4 |
| 16 | 20.34 | 3.68 | 3 |
| 17 | 20.67 | 3.62 | 22 |
| 18 | 22.50 | 3.27 | 25 |
| 19 | 23.91 | 3.20 | 74 |
This crystal formation infrared spectrogram (KBr pressed disc method mensuration), at 3242.09 ± 5 cm-1、3034.55±5 cm-1、
1337.58±5 cm-1With 1064.18 ± 5cm-1There is characteristic peak at place.
INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer；CuKa 40Kv 100mA；2 θ scannings
Scope: 0-50°。
Embodiment 2
Containing Parecoxib Sodium without the injection of hydrate
Prescription: Parecoxib Sodium without hydrate (20g based on Parecoxib), disodium hydrogen phosphate 3g, sodium dihydrogen phosphate 0.5g,
Phosphoric acid/Sodium hydroxide q. s, water for injection 2L, makes 1000.
Technique: take recipe quantity 90% water for injection, the disodium hydrogen phosphate and the sodium dihydrogen phosphate stirring that are initially charged recipe quantity are the most molten
Solve, add 0.1mol/L phosphoric acid or sodium hydrate aqueous solution, tune pH, then in solution, add the Parecoxib Sodium of recipe quantity, stir
Mix to dissolving completely；Add 0.1% pin charcoal of this amount of solution, place 15 minutes, filter, add to the full amount of water for injection；Add
0.1mol/L phosphoric acid or sodium hydrate aqueous solution, tune pH value, fine straining, Quality control of intermediates, fill, half tamponade is good by subpackage
Sample, load in freeze dryer, freezing, be dried, tamponade, outlet, obtain Parecoxib sodium pharmaceutical composition.
Claims (6)
1. the anhydrous compound crystal of Parecoxib Sodium shown in formula I,
(I)
The crystal of described Parecoxib Sodium anhydrous compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has
There are the following 2 θ angles of diffraction and d value,
The error of the 2 θ angles of diffraction is ± 0.2.
2. Parecoxib Sodium anhydrous compound crystal as claimed in claim 1, infrared spectrogram, pellet technique measures,
3242.09±5 cm-1、3034.55±5 cm-1、1337.58±5 cm-1With 1064.18 ± 5cm-1There is characteristic peak at place.
3. the preparation method of Parecoxib Sodium anhydrous compound crystal described in claim 1, by adding 4-by Parecoxib Sodium
5 times of weigh-volume ratios, in heptane, do not put into crystal seed, use vigorous magnetic stirring to be heated to reflux 6 hours by the suspension of acquisition,
Being collected by vacuum filtration crystal, at 40 DEG C, dried in vacuum overnight obtains Parecoxib Sodium anhydrous compound.
4. the anhydrous compound crystal containing Parecoxib Sodium described in claim 1 is pharmaceutically acceptable with one or more
The compositions of Parecoxib Sodium anhydrous compound of carrier composition.
5. compositions as claimed in claim 4, it is characterised in that said composition is used for preparing injection.
6. the anhydrous compound crystal of Parecoxib Sodium described in claim 1 is manufacturing treatment Transitional cell carcinomas (COX-2) mediation
Disease medicine in application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310395826.8A CN104418818B (en) | 2013-09-04 | 2013-09-04 | Parecoxib sodium anhydrous compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310395826.8A CN104418818B (en) | 2013-09-04 | 2013-09-04 | Parecoxib sodium anhydrous compound |
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| CN104418818A CN104418818A (en) | 2015-03-18 |
| CN104418818B true CN104418818B (en) | 2017-01-11 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107056721B (en) * | 2017-04-12 | 2019-09-06 | 山东裕欣药业有限公司 | A kind of Parecoxib Sodium crystalline compounds and preparation method thereof |
| CN108969494A (en) * | 2018-09-25 | 2018-12-11 | 珠海赛隆药业股份有限公司 | A kind of Parecoxib Sodium durative action preparation and preparation method thereof |
| CN109369552A (en) * | 2018-12-13 | 2019-02-22 | 江苏奥赛康药业股份有限公司 | A kind of SC 69124 sodium novel crystal form and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216043A (en) * | 1996-04-12 | 1999-05-05 | G·D·瑟尔公司 | Substd. benzenesulfonamide derivs as prodrugs of COX-2 inhibitors |
| CN1578774A (en) * | 2001-10-02 | 2005-02-09 | 法玛西雅公司 | Method for preparing benzenesulfonyl compounds |
| EP1550658A1 (en) * | 2003-12-30 | 2005-07-06 | Dr. Reddy's Laboratories Ltd. | Method for preparing 3,4-diphenyl-substituted isoxazole compounds |
-
2013
- 2013-09-04 CN CN201310395826.8A patent/CN104418818B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216043A (en) * | 1996-04-12 | 1999-05-05 | G·D·瑟尔公司 | Substd. benzenesulfonamide derivs as prodrugs of COX-2 inhibitors |
| CN1578774A (en) * | 2001-10-02 | 2005-02-09 | 法玛西雅公司 | Method for preparing benzenesulfonyl compounds |
| EP1550658A1 (en) * | 2003-12-30 | 2005-07-06 | Dr. Reddy's Laboratories Ltd. | Method for preparing 3,4-diphenyl-substituted isoxazole compounds |
Non-Patent Citations (1)
| Title |
|---|
| "N-[[(5-Methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl] propanam ide, Sodium Salt, Parecoxib Sodium: A Potent and Selective Inhibitor of COX-2 for Parenteral Administration";John J. Talley, et al.;《J. Med. Chem.》;20000504;第43卷(第9期);1661-1663，SI * |
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